MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer

Cancer Lett. 2015 Jul 10;363(1):17-27. doi: 10.1016/j.canlet.2015.03.026. Epub 2015 Mar 24.

Abstract

Altered levels and functions of microRNAs (miRs) have been associated with carcinogenesis. In this study, we investigated the role of miR-124 in colorectal adenoma (CRA) and cancer (CRC). The expression levels of miR-124 were decreased in CRA (81.8%) and CRC (57.6%) in 55 clinical samples. The ectopic expression of miR-124 induced apoptosis and autophagy in colon cancer cells. Also, miR-124 targeted polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of pyruvate kinase muscles 1 and 2 (PKM1 and PKM2) and induced the switching of PKM isoform expression from PKM2 to PKM1. Also, siR-PTB1 induced drastic apoptosis in colon cancer cells. Furthermore, we found that the ectopic expression of miR-124 enhanced oxidative stress and the miR-124/PTB1/PKM1/PKM2 axis constituted a feedback cascade. Finally, we showed that intratumor injection of miR-124 and siR-PTB1 induced a tumor-suppressive effect in xenografted mice. The axis was established by both in vitro and in vivo experiments to function in human colorectal cancer cells. These findings suggest that miR-124 acts as a tumor-suppressor and a modulator of energy metabolism through a PTB1/PKM1/PKM2 feedback cascade in human colorectal tumor cells.

Keywords: Colorectal cancer; PKM; PTB1; Warburg effect; miR-124.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Apoptosis
  • Autophagy
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Case-Control Studies
  • Cell Line, Tumor
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy
  • Energy Metabolism
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genetic Therapy / methods
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / administration & dosage
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oxidative Stress
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • RNA Interference
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • Time Factors
  • Transfection
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • 3' Untranslated Regions
  • Carrier Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • MIRN124 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • PTBP1 protein, human
  • Thyroid Hormones
  • Polypyrimidine Tract-Binding Protein